Mitochondria play a central role in energy metabolism and redox regulation. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging of various tissues, including the heart. The aging heart is subjected to cardiac hypertrophy, especially when under mechanical stress, such as left ventricular pressure overload. ATP synthase is a key enzyme complex generating ATP in mitochondria, thus playing a central role in mitochondrial function. Functional defects of ATP synthase can cause and aggravate human diseases, such as cardiomyopathy and congestive heart failure, especially in aging population. However, it remains unclear if impaired mitochondrial ATP synthase is one of the underlying mechanism of energy deficiency and mitochondrial dysfunction in the aging heart. We have recently identified a PPAR-target gene encoding a novel mitochondrial protein ES1. Preliminary studies revealed that ES1 is a mitochondrial protein interacting with the subunits ? and ? of ATP synthase F1 sector. ES1 appears to be an enhancer of ATP production by increasing ATP synthesis and an inhibitor of ATP hydrolysis. However, it remains unknown if ES1 similarly regulates ATP production in the heart. Interestingly, our preliminary studies revealed that ES1 protein levels were decreased in the hearts from 14 month-old mice. Based on the pilot studies on conditional transgenic and gene targeting mouse lines, we hypothesize that ES1 is a novel therapeutic target of protecting the heart from aging-relating cardiomyopathy. To test this central hypothesis, we will first determine whether gene therapy that increasing cardiac ES1 expression will protect the heart from aging-related hypertrophy. We will then define the underlying molecular and biochemical mechanisms by determining the role of ES1 as an endogenous regulator of ATP synthase and as a determinant of mitochondrial structure/function in the heart. We anticipate the proposed study will provide strong evidence supporting that ES1 is a crucial regulator of myocardial energy metabolism via its regulatory effects on the ATP synthase and mitochondrial structure/function. Result of this study will provide preclinical evidence that ES1 can be a new target for protecting the heart from aging related hypertrophy.